The role of Trained Immunity and Mitochondrial dysfunction on INnate immunity in children and adolescents aGing with PHIV (TIMING-PHIV)

训练免疫和线粒体功能障碍对感染 PHIV 的儿童和青少年先天免疫的作用 (TIMING-PHIV)

• 批准号: 10595053
• 负责人: Sahera Dirajlal-Fargo
• 金额: $ 75.81万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-21 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595053
• 关键词: Adherence; Adolescent; Adult; Aging; Area; Biological; Biological Assay; Cell physiology; Cells; Cellular Metabolic Process; Child; Chronic; Clinical; Collaborations; Cytometry; Data; Development; Environmental Risk Factor; Epigenetic Process; Exposure to; Flow Cytometry; Foundations; Functional disorder; Gastrointestinal tract structure; Gene Expression Profile; Gene Expression Profiling; Genetic Transcription; HIV; HIV Infections; HIV-infected adolescents; Immune; Immune System Diseases; Immune system; Immunity; Immunization; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Intervention Trial; Knowledge; Leukocytes; Link; Lipids; Lipopolysaccharides; Lymphocyte; Macrophage; Macrophage Activation; Malaria; Measurement; Measures; Mediator; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Myeloid Cells; Natural Immunity; Natural Killer Cells; Participant; Pathway interactions; Perinatal; Persons; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Process; Prophylactic treatment; Regimen; Reporting; Risk; Role; Signal Transduction; System; T-Cell Activation; Toxic effect; Training; Treatment-related toxicity; Trimethoprim-Sulfamethoxazole; Uganda; United States; Youth; acute infection; antiretroviral therapy; co-infection; cohort; comorbidity; cytokine; experimental study; gastrointestinal; geographic difference; gut dysbiosis; high dimensionality; immune activation; immune system function; immunoregulation; innovation; member; microbial; microbial products; mitochondrial dysfunction; monocyte; mortality; novel; pathogen; polyglucosan; prenatal therapy; prognostic; single-cell RNA sequencing; therapy development; vaccine development

Project Summary: Human immunodeficiency virus (HIV) is associated with persistent immune activation and dysfunction, even during suppressive antiretroviral therapy (ART) that was initiated early post-infection. Perinatally acquired HIV (PHIV) infection and lifelong ART likely alter the development and function of the immune system. The exposure of HIV and ART in utero, the decades of ART therapy, the lasting effects of older toxic ART with mitochondrial toxicity and the long-term sub-optimal adherence known to occur with prolonged ART use, heighten concern that sequelae of HIV and ART in children and adolescents may be more frequent and potentially more devastating than in adults. Better understanding of immune dysfunction in PHIV is crucial, as it is often easier to limit or even reverse comorbidities at an early stage. We are exploring the consequences of PHIV and its treatment with ART in a cohort of adolescents in Uganda and have reported significant differences in the immune profiles of HIV- and HIV+ children. These differences may be driven by trained immunity, a process by which cells of the innate immune system (e.g. monocytes, macrophages and natural killer cells) are reprogrammed to respond differently to subsequent exposure to microbial products and proinflammatory lipids. Recent studies, including our own, demonstrate that ART exposure may also contribute to alterations in immune cell activation, potentially through decreased mitochondrial function and through modulation of intracellular signaling cascades. The knowledge gained from this proposal could be substantial, and from a translational perspective will lay the foundation to identify key pathways with biological, clinical, and prognostic relevance for adolescents who are advancing into adulthood. These results could inform intervention trials to mitigate the development of comorbidities associated with immune activation. We propose: Aim 1: To measure innate immune profiles (i.e monocytes and NK cells) in adolescents with and without HIV in Uganda and the United States. Aim 2: To identify the role of trained immunity in innate immune modulation in adolescents with and without HIV infection in Uganda. Aim 3: To evaluate how mitochondrial function plays a role in innate immune profiles longitudinally in adolescents with and without HIV in Uganda. This proposal combines a well-characterized cohort of children with and without PHIV with ex vivo and in vitro assessments of immune cell phenotype and function. We will use high-dimensional flow cytometry analyses, single cell transcriptional profiling, and an in-depth analytical approach to define the potential mechanisms whereby chronic exposure to ART, microbial products, and clinical and environmental factors may contribute to innate immune cell activation or dysfunction. This is a continuation of a highly successful collaboration among the study team members and we are well positioned to perform this innovative project.

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